Abstract 4620: Development of orthotopic breast cancer brain metastasis patient-derived xenograft(PDX) model

Abstract

Background: The vast majority of the mortality of breast cancer results from distant metastasis and pre-clinical models are in critical need for effective drug development. Patient-derived xenograft (PDX) maintains the features of the donor tumors such as intra-tumor heterogeneity; however, PDX model of breast cancer brain metastasis that delivers stable consistent results is not popularized. We demonstrate our novel methods (coined "Oshi"method) used to develop an orthotopic brain metastasis patient-derived xenograft model (PDMOX) for breast cancer brain metastasis via tumor tissue implantation. Methods: Brain metastasis PDX were created using metastatic brain tumors from breast cancer patients and implanting them in the brain of NSG female mice. Tumors of ~1 mm3 were implanted mechanically minced tissue with medium. We implant the tissue through a frontal bone burr hole into the right caudate putamen. Tumor growth was monitored by magnetic resonance imaging (MRI). Results: "Oshi" method utilizes a pipette tip in order to inoculate tumor at the same depth. A minced tumor was instilled using a 23G needle as the "non-oshi" method. One hour post-surgical survival after implantation of minced tumor by "non-oshi" method was only 37.5% (3/8), whereas 100% (40/40) by the "Oshi" method. All tumors were well engrafted in surviving mice after both methods. There was larger variation in tumor growth after "non-oshi" (Median 20±25.0 day, range: 12-24 day. Tumor volume: median 5.6±21.0 mm3, range 2.8-48.7 mm3). One mouse developed ptosis, and 2 out of 3 mice that underwent the "non-oshi" method had sudden death. On the other hand, all mice that underwent the "Oshi" method lived until the tumor grew to 125-200 mm3 without neurological symptoms. The engraftment rate of Mincing tumor were 100% at 1.5 months after implantation, while the engraftment rate of Enzymatic digestion tumors was only 50% at 2 months. Mincing tumor had faster growth speed than the tumor of enzymatic digestion. The engraftment time of enzymatic digestion tumor was slower than other tumor tissue forms. All 3rd generation tumors could be detected at the point of 1month after implantation, on the other hand, it took 2 month to detect 1st generation tumors. The growth of 3rd generation tumors was significantly faster and bigger than others. Conclusion: Various surgical techniques used to generate PDMOX breast cancer models showed major differences in the tumors and outcomes. These novel models are expected to become powerful tools for preclinical studies in metastatic breast cancer.Citation Format: Masanori Oshi. Development of orthotopic breast cancer brain metastasis patient-derived xenograft(PDX) model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4620.